Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Department of Chemistry, The Pennsylvania State University, University Park, PA, 16802, USA.
Nat Commun. 2020 Dec 9;11(1):6310. doi: 10.1038/s41467-020-20145-9.
Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we identify a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We find that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [FeS] cluster acquisition and coordination. The enzymatic activity of human ALAD is greatly reduced upon loss of its Fe-S cluster, which results in reduced heme biosynthesis in human cells. As ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway, our findings help explain why heme biosynthesis depends on intact ISC biogenesis.
血红素生物合成和铁硫簇（ISC）生物合成是两种需要铁的主要哺乳动物代谢途径。长期以来，人们一直知道这两种途径相互关联，但以前描述的相互作用并不能完全解释为什么血红素生物合成依赖于完整的 ISC 生物合成。在此，我们通过发现催化血红素生物合成第二步的人氨基酮戊酸脱水酶（ALAD）是一种 Fe-S 蛋白，从而确定了这两种途径之间以前未被识别的联系。我们发现，人 ALAD 的几个高度保守的半胱氨酸残基和 Ala306-Phe307-Arg308 基序对于[FeS]簇的获取和配位很重要。人 ALAD 的酶活性在其 Fe-S 簇丢失后大大降低，导致人细胞中的血红素生物合成减少。由于 ALAD 在血红素生物合成途径中提供了一个早期依赖 Fe-S 的检查点，我们的发现有助于解释为什么血红素生物合成依赖于完整的 ISC 生物合成。
